PDGF-D is a recently discovered member of the platelet-derived growth factor (PDGF) family (Bergsten et al., Nature Cell Biol. 3:512–516, 2001; LaRochelle et al., Nature Cell Biol. 3:517–521, 2001). PDGF-D is also referred to as “zvegf4” (WIPO Publication WO 00/66736).
The PDGF-D polypeptide has a multidomain structure that comprises an amino-terminal CUB domain and a carboxyl-terminal growth factor domain joined by an interdomain region of approximately 70 amino acid residues. The growth factor domain of PDGF-D, which comprises approximately residues 250–370 of SEQ ID NO:2, is characterized by an arrangement of cysteine residues and beta strands that is characteristic of the “cystine knot” structure of the PDGF family. The CUB domain shows sequence homology to CUB domains in the neuropilins (Takagi et al., Neuron 7:295–307, 1991; Soker et al., Cell 92:735–745, 1998), human bone morphogenetic protein-1 (Wozney et al., Science 242:1528–1534, 1988), porcine seminal plasma protein and bovine acidic seminal fluid protein (Romero et al., Nat. Struct. Biol. 4:783–788, 1997), and Xenopus laevis tolloid-like protein (Lin et al., Dev. Growth Differ. 39:43–51, 1997).
PDGF-D forms a homodimeric protein (PDGF-DD) that is proteolytically cleaved to produce the active species, a growth factor domain dimer. The active protein binds to and activates the β/β and α/β isoforms of the PDGF receptor on the cell surface. PDGF-DD dimers are mitogenic for a variety of mesenchymal cells (Bergsten et al. ibid.; LaRochelle et al., ibid.). In addition, PDGF-D has been shown to have bone-forming activity in mice (WIPO publication WO 01/57083).